TY - JOUR
T1 - Molecular and structural traits of insulin receptor substrate 1/LC3 nuclear structures and their role in autophagy control and tumor cell survival
AU - Lassak, Adam
AU - Dean, Mathew
AU - Wyczechowsk, Dorota
AU - Wilk, Anna
AU - Marrero, Luis
AU - Trillo-Tinoco, Jimena
AU - Hamid Boulares, A.
AU - Sarkaria, Jann N.
AU - Valle, Luis Del
AU - Peruzzi, Francesca
AU - Ochoa, Augusto
AU - Reiss, Krzysztof
N1 - Publisher Copyright:
© 2018 American Society for Microbiology.
PY - 2018/5/1
Y1 - 2018/5/1
N2 - Insulin receptor substrate 1 (IRS-1) is a common cytosolic adaptor molecule involved in signal transduction from insulin and insulin-like growth factor I (IGF-I) receptors. IRS-1 can also be found in the nucleus. We report here a new finding of unique IRS-1 nuclear structures, which we observed initially in glioblastoma biopsy specimens and glioblastoma xenografts. These nuclear structures can be reproduced in vitro by the ectopic expression of IRS-1 cDNA cloned in frame with the nuclear localization signal (NLS-IRS-1). In these structures, IRS-1 localizes at the periphery, while the center harbors a key autophagy protein, LC3. These new nuclear structures are highly dynamic, rapidly exchange IRS-1 molecules with the surrounding nucleoplasm, disassemble during mitosis, and require a growth stimulus for their reassembly and maintenance. In tumor cells engineered to express NLS-IRS-1, the IRS-1/LC3 nuclear structures repress autophagy induced by either amino acid starvation or rapamycin treatment. In this process, IRS-1 nuclear structures sequester LC3 inside the nucleus, possibly preventing its cytosolic translocation and the formation of new autophagosomes. This novel mechanism provides a quick and reversible way of inhibiting autophagy, which could counteract autophagy-induced cancer cell death under severe stress, including anticancer therapies.
AB - Insulin receptor substrate 1 (IRS-1) is a common cytosolic adaptor molecule involved in signal transduction from insulin and insulin-like growth factor I (IGF-I) receptors. IRS-1 can also be found in the nucleus. We report here a new finding of unique IRS-1 nuclear structures, which we observed initially in glioblastoma biopsy specimens and glioblastoma xenografts. These nuclear structures can be reproduced in vitro by the ectopic expression of IRS-1 cDNA cloned in frame with the nuclear localization signal (NLS-IRS-1). In these structures, IRS-1 localizes at the periphery, while the center harbors a key autophagy protein, LC3. These new nuclear structures are highly dynamic, rapidly exchange IRS-1 molecules with the surrounding nucleoplasm, disassemble during mitosis, and require a growth stimulus for their reassembly and maintenance. In tumor cells engineered to express NLS-IRS-1, the IRS-1/LC3 nuclear structures repress autophagy induced by either amino acid starvation or rapamycin treatment. In this process, IRS-1 nuclear structures sequester LC3 inside the nucleus, possibly preventing its cytosolic translocation and the formation of new autophagosomes. This novel mechanism provides a quick and reversible way of inhibiting autophagy, which could counteract autophagy-induced cancer cell death under severe stress, including anticancer therapies.
KW - Autophagy
KW - Cellular distribution
KW - Fluorescence recovery after photobleaching
KW - Glioblastoma
KW - Multiprotein complexes
KW - Nuclear suborganelle
KW - Phase transition
KW - Protein binding
KW - Signal transduction
UR - http://www.scopus.com/inward/record.url?scp=85046535550&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85046535550&partnerID=8YFLogxK
U2 - 10.1128/MCB.00608-17
DO - 10.1128/MCB.00608-17
M3 - Article
C2 - 29483302
AN - SCOPUS:85046535550
SN - 0270-7306
VL - 38
JO - Molecular and cellular biology
JF - Molecular and cellular biology
IS - 10
M1 - e00608
ER -